Santourlidis Simeon, Wernet Peter, Ghanjati Foued, Graffmann Nina, Springer Judith, Kriegs Christian, Zhao Xiaoyi, Brands Jens, Araúzo-Bravo Marcos Jesus, Neves Rui, Koegler Gesine, Uhrberg Markus
Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany.
Stem Cell Res. 2011 Jan;6(1):60-9. doi: 10.1016/j.scr.2010.08.003. Epub 2010 Aug 27.
Unrestricted somatic stem cells (USSC) from human cord blood display a broad differentiation potential for ectodermal, mesodermal, and endodermal cell types. The molecular basis for these stem cell properties is unclear and unlike embryonic stem cells (ESC) none of the major stem cell factors OCT4, SOX2, and NANOG exhibits significant expression in USSC. Here, we report that these key stem cell genes hold an epigenetic state in between that of an ESC and a terminally differentiated cell type. DNA methylation analysis exhibits partial demethylation of the regulatory region of OCT4 and a demethylated state of the NANOG and SOX2 promoter/enhancer regions. Further genome-wide DNA methylation profiling identified a partially demethylated state of the telomerase gene hTERT. Moreover, none of the pluripotency factors exhibited a repressive histone signature. Notably, SOX2 exhibits a bivalent histone signature consisting of the opposing histone marks dimeH3K4 and trimeH3K27, which is typically found on genes that are "poised" for transcription. Consequently, ectopic expression of OCT4 in USSC led to rapid induction of expression of its known target gene SOX2. Our data suggest that incomplete epigenetic repression and a "poised" epigenetic status of pluripotency genes preserves the USSC potential to be able to react adequately to distinct differentiation and reprogramming cues.
来自人脐带血的无限制体细胞干细胞（USSC）对外胚层、中胚层和内胚层细胞类型具有广泛的分化潜能。这些干细胞特性的分子基础尚不清楚，与胚胎干细胞（ESC）不同，主要干细胞因子OCT4、SOX2和NANOG在USSC中均未表现出明显表达。在此，我们报告这些关键干细胞基因处于ESC和终末分化细胞类型之间的表观遗传状态。DNA甲基化分析显示OCT4调控区域部分去甲基化，NANOG和SOX2启动子/增强子区域处于去甲基化状态。进一步的全基因组DNA甲基化谱分析确定了端粒酶基因hTERT处于部分去甲基化状态。此外，多能性因子均未表现出抑制性组蛋白特征。值得注意的是，SOX2表现出由相反的组蛋白标记二甲基化H3K4和三甲基化H3K27组成的双价组蛋白特征，这通常在“准备好”转录的基因上发现。因此，在USSC中异位表达OCT4会导致其已知靶基因SOX2的表达迅速诱导。我们的数据表明，多能性基因的不完全表观遗传抑制和“准备好”的表观遗传状态保留了USSC对不同分化和重编程信号做出充分反应的潜能。
